The studies outlined in this grant are concerned with the interrelationships between immunosuppressive and lymphocytotoxic activities of several cytotoxic drugs. Because of their defined kinetic behavior and the availability of in vitro assays, particular emphasis has been placed on alterations in the numbers and the functional activities of T-lymphocytes. In guinea pigs, studies demonstrated that the immunosuppressive activities of two phase-specific drugs, 6-MP and methotrexate, and a cycle-specific agent, cyclophosphamide correlated closely with the proliferative activities of target lymphocytes. The phase-specific drugs are primarily active against clones of proliferating lymphocytes; cycle-specific agents are effective against both intermitotic and cycling T-cells. Additional studies are now in progress which are evaluating the susceptibility of T- and B-lymphocytes to individual agents. T-cells are quantitated using the rabbit-erythrocyte rosette assay; B-cells by complement rosettes. Initial studies have shown the marked toxicity of cyclophosphamide for both types. In parallel investigations, the selectivity of these agents are being assessed by simultaneously measuring cellular and humoral immunity to a single antigen, KLH. These studies, in addition to defining the effects of drugs at different time intervals in an immune response, these data will be applied to an assessment of multiple drug protocols. Combination of agents may provide a more effective means of suppressing a particular immune response than can be achieved with a single agent. BIBLIOGRAPHIC REFERENCES: Perchick, J. S., Winkelstein, A., and Shadduck, R. K. Disseminated intravascular coagulation in heat stroke: Response to heparin therapy. J. Am. Med. Assoc. 231:480-483, 1975. Winkelstein, A. and Rabin, B. S. Lymphocyte Biology. Bull. Rheumatic Dis. 25:816-821, 822-882, 1975.